Asymmetric
Aza-Wacker-Type Cyclization of N‑Ts Hydrazine-Tethered
Tetrasubstituted Olefins:
Synthesis of Pyrazolines Bearing One Quaternary or Two Vicinal Stereocenters
posted on 2018-05-26, 00:00authored byXuezhen Kou, Qihang Shao, Chenghao Ye, Guoqiang Yang, Wanbin Zhang
We
have developed an asymmetric aza-Wacker-type cyclization of N-Ts hydrazine-tethered tetrasubstituted olefins, affording
optically active pyrazolines bearing chiral tetrasubstituted carbon
stereocenters. This reaction is tolerant to a broad range of substrates
under mild reaction conditions, giving the desired chiral products
with high enantioselectivities. Generation of two vicinal stereocenters
on the CC double bonds was also achieved with high selectivities,
a process which has been rarely studied for Wacker-type reactions.
A mechanistic study revealed that this aza-Wacker-type cyclization
undergoes a syn-aminopalladation process. It was
also found that for substrates bearing two linear alkyl substituents
on the outer carbon atom of the olefin, both of which are larger than
a methyl group, the alkyl substituent that is cis to the intranucleophilic group participates more readily in β-hydride
elimination. When one of the two alkyl substituents on the outer carbon
atom of the olefin is a methyl group, β-hydride elimination
proceeds selectively at the methylene side, thus both diastereomers
can be prepared via switching the configuration of the olefin. Furthermore,
the product can be converted to a pharmaceutical compound in high
yields over three steps.